Residual Infestation and Recolonization during Urban Triatoma infestans Bug Control Campaign,Peru

Chagas disease vector control campaigns are being conducted in Latin America, but little is known about medium-term or long-term effectiveness of these efforts, especially in urban areas. After analyzing entomologic data for 56,491 households during the treatment phase of a Triatoma infestans bug control campaign in Arequipa, Peru, during 2003–2011, we estimated that 97.1% of residual infestations are attributable to untreated households. Multivariate models for the surveillance phase of the campaign obtained during 2009–2012 confirm that nonparticipation in the initial treatment phase is a major risk factor (odds ratio [OR] 21.5, 95% CI 3.35–138). Infestation during surveillance also increased over time (OR 1.55, 95% CI 1.15–2.09 per year). In addition, we observed a negative interaction between nonparticipation and time (OR 0.73, 95% CI 0.53–0.99), suggesting that recolonization by vectors progressively dilutes risk associated with nonparticipation. Although the treatment phase was effective, recolonization in untreated households threatens the long-term success of vector control.     

Escaping from Flatland: Antimalarial Activity of sp3-Rich Bridged Pyrrolidine Derivatives

We utilized synthetic photochemistry to generate novel sp³-rich scaffolds and report the design, synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]hexane scaffold. Preliminary antimalarial screening of the library provided promising compounds with activity in the 1–5 μM range with an enhanced hit rate. Further evaluation (solubility, drug metabolism and pharmacokinetics (DMPK), and toxicity) of a selected compound (9) suggested that this series represents an excellent opportunity for further optimization with the framework offering multiple opportunities for the addition of uniquely vectorally positioned extra functionality.     

Effect of build orientation on the manufacturing process and the properties of stereolithographic dental ceramics for crown frameworks

Statement of problemStereolithography (SLA) ceramic crown frameworks are suitable for clinical use, but the impact of SLA build orientation has not been identified.PurposeThe purpose of this in vitro study was to investigate the effect of 3 build orientations on the physical and mechanical properties and the microstructure of SLA alumina dental ceramics.Material and methodsThe physical and mechanical properties and microstructures of 3 different oriented SLA alumina ceramics (ZX, ZY, and XY) were evaluated by visual observation, hydrostatic weighing (n=10/group), Weibull analyses (n=30/group), scanning electron microscopy, 3-point flexural strength (n=30/group), fracture toughness (indentation, single-edge-V-notched-beam) (n=4/group), and Vickers hardness (n=15/group) testing. The hydrostatic weighing, 3-point flexural strength, fracture toughness, and Vickers hardness testing data were statistically analyzed (α=.05).ResultsThe minimum resting period of slurries between the polymerization of 2 layers was shorter for the ZY- and ZX-oriented specimens and increased with the layer surface. The density and Vickers hardness of the SLA-manufactured specimens were similar for all groups (P>.05). The 95% confidence intervals of the Weibull moduli of the ZX- and ZY-oriented specimens were higher than that of the XY-oriented specimens, with no overlap fraction. The ZY-oriented specimens displayed significantly higher 3-point flexural strength (P<.05) and fracture toughness as evaluated by the single-edge-V-notched-beam method than the ZX-oriented specimens (P<.05). They also displayed significantly higher 3-point flexural strength than the XY-oriented specimens (P<.05). The microstructural analysis showed that the texturing was heterogeneous and that the major axis of the large grains of alumina ran parallel to the orientation of the layers.ConclusionsThe ZY orientation produced a reliable dental ceramic by SLA, with the shortest general manufacturing time and the highest mechanical strength when the layers were perpendicular to the test load surface.     

Rescuing the physician-scientist workforce: the time for action is now

The 2014 NIH Physician-Scientist Workforce (PSW) Working Group report identified distressing trends among the small proportion of physicians who consider research to be their primary occupation. If unchecked, these trends will lead to a steep decline in the size of the workforce. They include high rates of attrition among young investigators, failure to maintain a robust and diverse pipeline, and a marked increase in the average age of physician-scientists, as older investigators have chosen to continue working and too few younger investigators have entered the workforce to replace them when they eventually retire. While the policy debates continue, here we propose four actions that can be implemented now. These include applying lessons from the MD-PhD training experience to postgraduate training, shortening the time to independence by at least 5 years, achieving greater diversity and numbers in training programs, and establishing Physician-Scientist Career Development offices at medical centers and universities. Rather than waiting for the federal government to solve our problems, we urge the academic community to address these goals by partnering with the NIH and national clinical specialty and medical organizations.In June 2014, the NIH Physician-Scientist Workforce (PSW) Working Group completed a year of data collection and deliberation, and released a report about the status of the PSW (1). The report is a combination of good news and bad news. The good news is that, despite the decline in the NIH budget, the size of the PSW has remained relatively stable. The bad news is that the current demographics, diversity, and career progression of this workforce raise concerns about the future. For a start, although apparently stable in size, the PSW is even smaller than many of us realized, and the apparent stability has hidden important demographic trends. In American Medical Association surveys of the nearly 1 million (and rising) MD physicians in the United States, only 14,000 (1.5%) consider research to be their primary focus (1). Even fewer have NIH grant support; only 8,200 physicians are principal investigators on NIH grants, split evenly between MDs and MD-PhDs (1). The number of extramural NIH-funded physician-scientists with research program (R series) awards has been essentially constant for the past 20 years, while the number of nonphysician (PhD) NIH-funded investigators has increased by half over the same period, reaching 19,400 in 2012 (1). As a result, the percentage of NIH awardees who are physicians has fallen to 30%. Although public policies have encouraged an increase in the number of medical schools and medical students in the US, and medical school admission policies have placed value on undergraduate research, the percentage of physicians focused on research has fallen.At the same time that the PSW has remained stable in size, data in the report show that the average age of the workforce is rising, as older investigators remain employed and younger investigators have not emerged in sufficient numbers. The average age at which a physician-scientist received his or her first NIH R01 grant in 2011 was 44 years for MD-PhDs and 45 years for MDs: approximately 10 years older than in 1980 (2). R01-funded investigators (physicians and nonphysicians) younger than 37 years have all but disappeared, and the time from graduating medical school to obtaining a first faculty position has increased to over 10 years for MD-PhDs and even longer for MDs without a PhD. Women and minorities are underrepresented, having opted not to enter or remain in the workforce. Thus, gathering places for physician-scientists look mostly like clubs for older white men. Without corrective action, the PSW appears headed for a population crash as older investigators retire. We recognize that younger physician-scientists have not entirely disappeared; they just take longer to obtain faculty appointments and independent NIH grants. This situation creates an extended waiting period that we call the holding zone, which contributes to the disturbing demographics (Figure 1).Open in a separate windowFigure 1The physician-scientist pipeline: long and leaky.The figure highlights a number of issues, including career attrition at every stage and the existence of a protracted period when well-trained physicians in their 30s are serving in subordinate positions awaiting the next step in their career progression. To draw attention to their plight, we call this period the holding zone. The illustration is based on the experience of MD-PhD program graduates, but many of the issues reflect the obstacles for any would-be physician-scientist. Attrition rates from MD-PhD programs are low, with most of those who withdraw completing medical school or graduate school. Very few MD-PhD program graduates (5% or fewer) choose to forego postgraduate clinical training as residents and fellows. In our experience, career attrition takes many forms and becomes cumulative at each stage, reflecting the proportion of individuals who either never return to research, opt for full-time clinical practice outside of academia, join academia as an assistant professor but spend their time caring for patients, or are appointed to the tenure track but end up devoting minimal time to research (1). A declaration of success depends in part on the definition of success. Outcome data show that approximately 80% of MD-PhD program graduates are working in academia, industry, or research institutes — including the NIH — but not all are doing research (3). Data on NIH award rates, conversions from K grants to R grants, and the proportion of individuals appointed to MSTP T32 grants can be found in the PSW report (1). The NIH continues to track principal investigators on grants but is just starting to track physician-scientists who play essential roles as other key personnel.     

Automated synthesis of 68Ga/177Lu-PSMA on the Trasis miniAllinOne

Prostate-specific membrane antigen (PSMA)-based radioligands for positron emission tomography (PET)/computed tomography (CT) studies represent the gold standard for detection of recurrent prostate cancer (PCa). [⁶⁸Ga]PSMA-HBED-CC is a PET radiotracer suitable for detection of PCa, and its clinical use has become widespread over the last few years. In this contribution, we detail our GMP-compliant production of [⁶⁸Ga]PSMA-HBED-CC using the Trasis miniAllinOne radiosynthesizer and report synthetic and clinical data for the first 100 productions of 2019. Additionally, we detail our efforts towards a GMP-compliant production of the radiotherapeutic [¹⁷⁷Lu]PSMA-I&T using the same synthesis module. PSMA-based radioligand therapy (RLT) offers a possible future treatment in cases of metastatic castration-resistant PCa, and GMP-compliant routine production methods are therefore called for. This report highlights how PSMA-based agents for theranostic purposes can be conveniently produced at a single radiochemistry Good Manufacturing Practice (GMP) site, thereby facilitating optimized detection and treatment of PCa.     

Local Discrete Velocity Grids for Multi-Species Rarefied Flow Simulations

This article deals with the derivation of an adaptive numerical method for mono-dimensional kinetic equations for gas mixtures. For classical deterministic kinetic methods, the velocity domain is chosen accordingly to the initial condition. In such methods, this velocity domain is the same for all time, all space points and all species. The idea developed in this article relies on defining velocity domains that depend on space, time and species. This allows the method to locally adapt to the support of the distribution functions. The method consists in computing macroscopic quantities by the use of conservation laws, which enables the definition of such local grids. Then, an interpolation procedure along with a upwind scheme is performed in order to treat the advection term, and an implicit treatment of the BGK operator allows for the derivation of an AP scheme, where the stability condition is independent of the relaxation rate. The method is then applied to a series of test cases and compared to the classical DVM method.